1. Field Of The Invention
The invention relates to a multistep process for the production of 5-alkyl tetramic acids from 4-alkyloxy- or 4-benzyloxy-3-pyrrolin-2-ones and aldehydes or ketones. It further relates to new 5-alkyl tetramic acids, which are accessible this way.
2. Background Art
5-Alkyl tetramic acids are valuable intermediate products for the production of beta-hydroxy-gamma-amino acids, such as, statine, which, for its part, plays an essential role as a structural element of renin inhibitors, such as, pepstatin or its analogs modified in the side chain. Renin inhibitors exhibit promising physiological effects and, therefore, are suitable for therapeutic purposes, especially as antihypertensive agents [H. J. Altenbach, Nachr. Chem. Tech. Lab. 36, 756 (1988)]. The tetramic acids can be present, depending on the conditions and the substituents, in the dione form, i.e., as pyrrolidine-2,4-dione, or in the enolone form, i.e., as 4-hydroxy-3-pyrrolin-2-one, or as mixture of the two forms. Only the dione form is represented below in each case regardless of the actual conditions.
So far there has been lacking simple and cost-favorable processes for the production of variously substituted 5-alkyl tetramic acids.
Thus, from Jouin et al., J. Chem. Soc. Perkin Trans. I, 1987. 1177, it is known to condense N-protected alpha-amino acids, after activation with chloroformic acid isopropenyl ester in the presence of 4-dimethylaminopyridine with Meldrum's acid, to the corresponding (1-hydroxyalkylidene) Meldrum's acids, which on heating in solution eliminate acetone and CO.sub.2 and are converted into the N-protected 5-substituted tetramic acids. Such process does yield optically active tetramic acid derivatives, if a start is made from optically active natural alpha-amino acids, but a whole series of expensive starting materials that are partially difficult to obtain or highly toxic, which in practice rules out a technical application.
Another drawback of such process is the limitation of the possibilities of variation of the substituents in the end product, which results from the fact that with the alpha-amino acids only a limited choice of substituents is available.
The same drawbacks are exhibited by an older process, which starts from alpha-amino acid esters, which are first reacted with malonic acid ester chlorides to the corresponding N-(alkoxycarbonylacetyl)-alpha-amino acid esters. The latter are cyclized to the 3-alkoxycarbonyl tetramic acids, which are converted into the corresponding 5-substituted tetramic acids by hydrolysis and decarboxylation. (T.P.C. Mulholland, R. Foster and D. B. Havdock, J. Chem. Soc. Perkin Trans. I 1972, 2121).